Academic journal article Environmental Health Perspectives

Quinones and Aromatic Chemical Compounds in Particulate Matter Induce Mitochondrial Dysfunction: Implications for Ultrafine Particle Toxicity

Academic journal article Environmental Health Perspectives

Quinones and Aromatic Chemical Compounds in Particulate Matter Induce Mitochondrial Dysfunction: Implications for Ultrafine Particle Toxicity

Article excerpt

Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)-enriched aromatic fraction in [O.sub.2.sup.*-] generation, decrease of membrane potential ([DELTA][PSI]m), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)--sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on [DELTA][PSI]m at high doses in calcium ([Ca.sup.2+])-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the [Ca.sup.2+] retention capacity at low doses and induced mitochondrial swelling and a decrease in [DELTA][PSI]m at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and [DELTA][PSI]m are mediated by adsorbed chemicals rather than the particles themselves. Key words: apoptosis, DEPs, diesel exhaust particles, PAHs, permeability transition pore, polycyclic aromatic hydrocarbons, quinones, ultrafine particles. Environ Health Perspect 112:1347-1358 (2004). doi:10.1289/ehp.7167 available via http://dx.doi.org/[Online 7 July 2004]

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There is increasing evidence that particulate pollutants induce inflammatory responses in the cardiorespiratory system (Nel et al. 1998; Nightingale et al. 2000; Saldiva et al. 2002). These proinflammatory effects have been linked to the ability of particulate matter (PM), such as diesel exhaust particles (DEPs), to generate reactive oxygen species (ROSs) and oxidative stress in macrophages, bronchial epithelial cells, and lung microsomes (Gurgueira et al. 2002; Hiura et al. 1999; Kumagai et al. 1997; Nel et al. 2001). The pro-oxidative effects of the intact particles can be mimicked by organic chemical components extracted from these particles (Hiura et al. 1999; Kumagai et al. 1997; Li et al. 2002). The PM-induced oxidative stress response is a hierarchical event, which is characterized by the induction of antioxidant and cytoprotective responses at lower tiers of oxidative stress and by pro-inflammatory and cytotoxic responses at higher levels of oxidative stress (Li et al. 2002; Xiao et al. 2003).

Mitochondrial damage is a key event in PM-induced cytotoxicity (Hiura et al. 1999, 2000). The initial response to PM is a decrease in mitochondrial membrane potential ([DELTA][PSI]m) and increased [O.sub.2.sup.*-] production, followed by cytochrome c release and inner mitochondrial membrane damage (Hiura et al. 1999, 2000; Upadhyay et al. 2003). It is also of interest that the smallest and potentially most toxic ambient particles, ultrafine particles (UFPs), lodge inside damaged mitochondria (Li et al. 2003). UFPs have a physical diameter < 0.1 [micro]m, which allows them to penetrate deep into the lung as well as into systemic circulation (Nemmar et al. 2002). Although it is still a matter of debate whether UFPs target the mitochondrion directly or enter the organelle secondary to oxidative damage (Li et al. 2003), PM-induced mitochondrial perturbation has important biologic effects, which include the initiation of apoptosis and decreased ATP production (Hiura et al. …

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